title: Energy metabolism and glutamate-glutamine cycle in the brain: a stoichiometric modeling perspective.
abstract: BACKGROUND
  The energetics of cerebral activity critically relies on the functional and metabolic interactions between neurons and astrocytes. Important open questions include the relation between neuronal versus astrocytic energy demand, glucose uptake and intercellular lactate transfer, as well as their dependence on the level of activity.
  
  
  RESULTS
  We have developed a large-scale, constraint-based network model of the metabolic partnership between astrocytes and glutamatergic neurons that allows for a quantitative appraisal of the extent to which stoichiometry alone drives the energetics of the system. We find that the velocity of the glutamate-glutamine cycle (Vcyc) explains part of the uncoupling between glucose and oxygen utilization at increasing Vcyc levels. Thus, we are able to characterize different activation states in terms of the tissue oxygen-glucose index (OGI). Calculations show that glucose is taken up and metabolized according to cellular energy requirements, and that partitioning of the sugar between different cell types is not significantly affected by Vcyc. Furthermore, both the direction and magnitude of the lactate shuttle between neurons and astrocytes turn out to depend on the relative cell glucose uptake while being roughly independent of Vcyc.
  
  
  CONCLUSIONS
  These findings suggest that, in absence of ad hoc activity-related constraints on neuronal and astrocytic metabolism, the glutamate-glutamine cycle does not control the relative energy demand of neurons and astrocytes, and hence their glucose uptake and lactate exchange.
authors.affiliation: Dipartimento di Fisica, Sapienza Università di Roma, P,le Aldo Moro 2, 00185 Roma, Italy. andrea.demartino@roma1.infn.it.
authors.forename: Francesco A
authors.initials: FA
authors.lastname: Massucci
authors.forename: Mauro
authors.initials: M
authors.lastname: DiNuzzo
authors.forename: Federico
authors.initials: F
authors.lastname: Giove
authors.forename: Bruno
authors.initials: B
authors.lastname: Maraviglia
authors.forename: Isaac Perez
authors.initials: IP
authors.lastname: Castillo
authors.forename: Enzo
authors.initials: E
authors.lastname: Marinari
authors.forename: Andrea
authors.initials: A
authors.lastname: De Martino
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D015203:Reproducibility of Results; D009435:Synaptic Transmission
chemical_list: D005973:Glutamine; D019344:Lactic Acid; D018698:Glutamic Acid; D005947:Glucose